rs397516363

chr15-63044075-G-Achr15-63044075-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP5_Moderate

The NM_001018005.2(TPM1):c.163G>A(p.Asp55Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D55G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.56

Genes affected

TPM1 (HGNC:12010): (tropomyosin 1) This gene is a member of the tropomyosin family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Tropomyosin is composed of two alpha-helical chains arranged as a coiled-coil. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments. The encoded protein is one type of alpha helical chain that forms the predominant tropomyosin of striated muscle, where it also functions in association with the troponin complex to regulate the calcium-dependent interaction of actin and myosin during muscle contraction. In smooth muscle and non-muscle cells, alternatively spliced transcript variants encoding a range of isoforms have been described. Mutations in this gene are associated with type 3 familial hypertrophic cardiomyopathy and dilated cardiomyopathy 1Y. [provided by RefSeq, Jun 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_001018005.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-63044075-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 691666.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, TPM1
• PP5: Variant 15-63044075-G-A is Pathogenic according to our data. Variant chr15-63044075-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43404.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM1	NM_001018005.2	c.163G>A	p.Asp55Asn	missense_variant	2/10	ENST00000403994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM1	ENST00000403994.9	c.163G>A	p.Asp55Asn	missense_variant	2/10	1	NM_001018005.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 20, 2011

The Asp55Asn variant has not been reported in the literature nor been previously identified by our laboratory. Aspartic acid (Asp) at amino acid position 55 is highly conserved across evolutionary distant species, increasing the likelihood that the change is pathogenic. In addition, this family?s racial origin is repor ted to be Caucasian and the Asp55Asn variant has not been identified in over 165 0 Caucasian probands tested by our laboratory (LMM unpublished data). This low f requency also supports a pathogenic role. Finally, this variant was predicted to be pathogenic using a novel computational tool, which was validated by our labo ratory using a set of cardiomyopathy variants with well-established clinical sig nificance. This tool's pathogenic prediction is estimated to be correct 94% of t he time, which suggests but does not prove that this variant is pathogenic (Jord an 2011). In summary, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
CardioboostCm	Uncertain	0.35
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.7	L;L;.;.;L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PROVEAN	Benign	-1.9	N;N;.;N;N;N;N;.
REVEL	Uncertain	0.40
Sift	Benign	0.20	T;D;.;T;T;D;D;.
Sift4G	Benign	0.55	T;T;T;T;T;T;T;.
Polyphen		0.33, 0.97	.;.;.;.;B;D;.;.
Vest4		0.70
MutPred		0.58		.;.;.;.;.;Loss of phosphorylation at T95 (P = 0.1089);.;.;
MVP		0.88
MPC		2.4
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.43
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397516363; hg19: chr15-63336274;